Although prevention of mother-to-child-transmission (PMTCT) with antiretroviral therapy has successfully reduced maternal HIV transmission, this leaves approximately 1.6 million HIV-exposed but uninfected (HEU) infants born annually. Despite the success of PMTCT, these children are not healthy. They are more likely to die or become sick during the first few months of life when compared to HIV-unexposed (HU) children and this is regardless of the mother's health or socioeconomic status. The vulnerability of these infants represents a major public health burden. We regard the unhealthy status of HEU infants to be based on a dysfunctional immune system, as these children respond poorly to vaccinations. Consequently, this study will focus on specific immunological abnormalities in these newborn infants. We have preliminary data showing that T cells in HEU newborn infants are highly activated, but have impaired function. We speculate that this is due to HIV exposure during pregnancy, or due to chronic maternal inflammation. We aim to seek a mechanism for impaired T cell immunity in these unhealthy infants and hypothesize that immune activation in the newborn results in increased frequencies of naturally occurring suppressor/regulatory cell populations, and that this is the basis for dysfunctional immunity. We will study the frequency and function of Myeloid Derived Suppressor Cells (MDSC) and T regulatory (Treg) cells and the effect these have on the infant's immunity to vaccines. Such an approach is entirely novel and our ability to explore newborn infant immunity will provide insight into how the health of these children is compromised. To address this hypothesis, we will use our established clinic in Khayelitsha, Cape Town, and enroll 100 HEU and 50 HU controls and follow them over 36 weeks. We will compare proportions of suppressor/regulatory cells and activated T cells at birth and after vaccination between HEU and healthy HU infants (Aim 1). We will collect cord blood to establish the immune status at birth and then measure T cell responses to Tetanus Toxoid and BCG on follow-up. We will also explore further mechanisms that result in the possible disruption of T cell functional pathways, by comparing the function and gene expression profiles of whole blood, MDSC and Treg cells between HEU and HU (Aim 2). We will use this approach to identify potential mechanisms to account for the inability of T cells in the HEU infant to functionally respond to vaccine antigens. This study brings together a wealth of expertise with investigators in the US and South Africa who are authorities in clinical, immunological and genomic analyses. This joint approach will be used to investigate the immune response of HIV-exposed infants to seek a mechanism for poor immunity at birth in these infants. The knowledge and insight gained from this study will lay the foundation for developing treatment strategies in these vulnerable children.